Journal of Inherited Metabolic Disease最新文献

{"title":"Performance of Relative Exchangeable Copper for the Diagnosis of Wilson Disease in Acute Liver Failure","authors":"Daniela Spirea,&nbsp;Claire Vanlemmens,&nbsp;François Parant,&nbsp;Teresa Antonini,&nbsp;Muriel Bost,&nbsp;Alain Lachaux,&nbsp;Abdelouahed Belmalih,&nbsp;Olivier Guillaud,&nbsp;Jerome Dumortier,&nbsp;Eduardo Couchonnal","doi":"10.1002/jimd.70024","DOIUrl":"https://doi.org/10.1002/jimd.70024","url":null,"abstract":"<p>Acute liver failure (ALF) can be one of the manifestations of Wilson disease (WD), and due to its severity, prompt diagnosis is essential. A ratio &gt; 15% of the exchangeable copper to total serum copper, known as relative exchangeable copper (REC), has been shown to have a 100% sensitivity and specificity for the diagnosis of WD but this has not yet been studied in an ALF setting. Patients diagnosed with ALF from 1 November 2011 to 31 December 2023, with available REC determination during the acute event, were included. Thirty-three patients were included (11 with WD and 22 without WD). The median age [IQR] at ALF was 12.9 [8.9–20.2] years, range: 0.6–71.0 years. Serum ceruloplasmin (Cp) &lt; 0.20 g/L and 24 h urinary copper excretion &gt; 1.6 μmol/L had both a sensitivity (Se) and specificity (Sp) for the diagnosis of WD of 100% and 72.7%, respectively. A ROC analysis of REC determined that the best cut-off point was 14.4% (AUC 1, <i>p</i> &lt; 0.01). All the WD patients had REC values &gt; 14.4%, yielding a sensitivity and specificity of 100. Relative exchangeable copper has 100% sensitivity and specificity for diagnosing Wilson disease in acute liver failure. Relative exchangeable copper has excellent performance in diagnosing Wilson disease in acute liver failure.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a (GSDIa)","authors":"David A. Weinstein,&nbsp;Terry G. Derks,&nbsp;David F. Rodriguez-Buritica,&nbsp;Ayesha Ahmad,&nbsp;María-Luz Couce,&nbsp;John J. Mitchell,&nbsp;Rebecca Riba-Wolman,&nbsp;Malaya Mount,&nbsp;Julieta Bonvin Sallago,&nbsp;Katalin M. Ross,&nbsp;Melanie M. van der Klauw,&nbsp;Foekje de Boer,&nbsp;Caroline van der Schaaf,&nbsp;Heather Saavedra,&nbsp;Miguel Martínez-Olmos,&nbsp;Elvis Atanga,&nbsp;Asad Hosseini,&nbsp;Deepali Mitragotri,&nbsp;Eric Crombez","doi":"10.1002/jimd.70014","DOIUrl":"https://doi.org/10.1002/jimd.70014","url":null,"abstract":"<p>Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno-associated virus serotype 8 vector expressing the human <i>G6PC1</i> gene that encodes G6Pase. This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 10¹² genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 10¹² GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment-emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); <i>p</i> &lt; 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions","authors":"Niamh X. Cawley,&nbsp;Ruyu Zhou,&nbsp;Nicole M. Farhat,&nbsp;James Iben,&nbsp;Derek M. Alexander,&nbsp;Rachel A. Luke,&nbsp;Cameron J. Padilla,&nbsp;Hibaaq O. Mohamed,&nbsp;Orsolya K. Albert,&nbsp;Kendall P. Robbins,&nbsp;Samar Rahhal,&nbsp;An Dang Do,&nbsp;Elizabeth Berry-Kravis,&nbsp;Stephanie M. Cologna,&nbsp;Fang Liu,&nbsp;Forbes D. Porter","doi":"10.1002/jimd.70016","DOIUrl":"https://doi.org/10.1002/jimd.70016","url":null,"abstract":"<p>Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. Aβ peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (<i>p</i> &lt; 0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (<i>r</i>_<i>s</i> = −0.42, FDR adj. <i>p</i> &lt; 0.0001) and increased with increased Annual Severity Increment Score (<i>r</i>_<i>s</i> = 0.52, FDR adj. <i>p</i> &lt; 0.0001). Baseline CSF total Tau levels were decreased 40% (<i>p</i> = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (<i>p</i> &lt; 0.0001, 95% CI 32%–47.4%). Longitudinal analysis also showed a significant (<i>p</i> = 0.004) decrease of 19% (95% CI 7%–30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Therapeutic Future for Congenital Disorders of Glycosylation","authors":"I. J. J. Muffels,&nbsp;T. Kozicz,&nbsp;E. O. Perlstein,&nbsp;E. Morava","doi":"10.1002/jimd.70011","DOIUrl":"https://doi.org/10.1002/jimd.70011","url":null,"abstract":"<div>\u0000 \u0000 <p>The past decade, novel treatment options for congenital disorders of glycosylation (CDG) have advanced rapidly. Innovative therapies, targeting both the root cause, the affected metabolic pathways, and resulting manifestations, have transitioned from the research stage to practical applications. However, with novel therapeutic abilities, novel challenges await, specifically when it concerns the large number of clinical trials that need to be performed in order to treat all 190 genetic defects that cause CDG known to date. The present paper aims to provide an overview of how the CDG field can keep advancing its therapeutic strategies over the coming years with these challenges in mind. We focus on three important pillars that may shape the future of CDG: the use of disease models, clinical trial readiness, and the possibility to make individualized treatments scalable to the entire CDG cohort.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects","authors":"Eva M. M. Hoytema van Konijnenburg,&nbsp;Joline Rohof,&nbsp;Gautam Kok,&nbsp;Peter M. van Hasselt,&nbsp;Clara D. van Karnebeek,&nbsp;Irena J. J. Muffels,&nbsp;Sabine A. Fuchs","doi":"10.1002/jimd.70017","DOIUrl":"https://doi.org/10.1002/jimd.70017","url":null,"abstract":"<p>Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are key enzymes for protein translation. The number of identified patients with recessive ARS1 deficiencies is rapidly increasing. Initially, only supportive care was available, but in recent years beneficial effects of targeted amino acid supplementation have been described. To allow early treatment and prevention of symptoms, rapid recognition is necessary, as well as insight into the natural history to evaluate treatment effects. We performed a scoping literature search for clinical characteristics and treatment effects of patients with ARS1 deficiencies. Symptoms were matched to Human Phenotype Ontology terms. We identified 438 patients with 20 different ARS1 deficiencies. Overall mortality was 22%. Neurological symptoms were most prevalent across all ARS1 deficiencies (in 87% of patients), including neurodevelopmental disorder (79%), microcephaly (50%) and seizures (46%). Growth issues and ophthalmological symptoms were also prevalent in many ARS1 deficiencies. Two distinct phenotypical clusters were seen: one with multisystemic disease including liver- and lung disease and another with a predominantly neurological phenotype. Supplementation with cognate amino acids was described in 21 patients, with beneficial effects (e.g., improvements in growth, development, liver and lung disease) in the majority. Treatment did not alleviate the most severe phenotypes. Specific symptoms relate to (a cluster of) specific ARS1 deficiencies; the mechanism is not yet understood. Multi-organ involvement should trigger inclusion of ARS1 genes in the diagnostic work-up. Treatment with cognate amino acids is promising, but it remains challenging to distinguish treatment effects from natural history. Synopsis: Treatment with cognate amino acids in ARS1 deficiencies is promising, but it remains challenging to distinguish treatment effects from natural history.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Normothermic Machine Perfusion of Explanted Human Metabolic Livers: A Proof of Concept for Studying Inborn Errors of Metabolism","authors":"Samira Safarikia,&nbsp;Riccardo Cirelli,&nbsp;Gionata Spagnoletti,&nbsp;Diego Martinelli,&nbsp;Giulia Bravetti,&nbsp;Paola Francalanci,&nbsp;Annamaria D'Alessandro,&nbsp;Giovina Di Felice,&nbsp;Marta Maistri,&nbsp;Elena Baldissone,&nbsp;Alberto M. Fratti,&nbsp;Raffaele Simeoli,&nbsp;Elisa Sacchetti,&nbsp;Sara Cairoli,&nbsp;Cristiano Rizzo,&nbsp;Rosanna Pariante,&nbsp;Michele Vacca,&nbsp;Andrea Cappoli,&nbsp;Christian Albano,&nbsp;Andrea Pietrobattista,&nbsp;Marco Spada,&nbsp;Carlo Dionisi Vici","doi":"10.1002/jimd.70010","DOIUrl":"https://doi.org/10.1002/jimd.70010","url":null,"abstract":"<p>The human liver plays a central metabolic role; however, its physiology may become imbalanced in inborn errors of metabolism (IEM), a broad category of monogenic disorders. Liver transplantation has been increasingly used to improve patient metabolic control, especially in diseases related to amino acid metabolism, such as urea cycle disorders and organic acidurias, to provide enzyme replacement. Ex vivo liver normothermic machine perfusion (NMP) techniques have recently been developed to increase the number of transplantable grafts and improve transplantation outcomes. This study used seven NMP of explanted livers from patients with IEM undergoing transplantation as models to investigate disease-related liver metabolism and function. The perfused livers demonstrated positive viability indicators and disease-specific targeted metabolomics providing the proof-of-principle that our ex vivo model expresses the biochemical disease characteristics and responds to therapeutical intervention in a unique “physiological” milieu, offering an ideal tool to study novel treatments, in a setting closely mirroring human disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy","authors":"Melissa A. King,&nbsp;Katherine C. Heger,&nbsp;Marija Drikic,&nbsp;Ayush Mandwal,&nbsp;Aneal Khan,&nbsp;David S. Sinasac,&nbsp;Keir Pittman,&nbsp;Edward L. Huttlin,&nbsp;Steven C. Greenway,&nbsp;Ian A. Lewis","doi":"10.1002/jimd.70018","DOIUrl":"https://doi.org/10.1002/jimd.70018","url":null,"abstract":"<p>The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood <i>DNAJC19</i> gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spermidine Treatment Improves GRIN2B Loss-Of-Function, A Primary Disorder of Glutamatergic Neurotransmission","authors":"A. Santos-Gómez,&nbsp;N. Juliá-Palacios,&nbsp;A. Rejano-Bosch,&nbsp;R. Marí-Vico,&nbsp;F. Miguez-Cabello,&nbsp;M. Masana,&nbsp;D. Soto,&nbsp;M. Olivella,&nbsp;À. García-Cazorla,&nbsp;X. Altafaj","doi":"10.1002/jimd.70015","DOIUrl":"https://doi.org/10.1002/jimd.70015","url":null,"abstract":"<p>GRIN-related disorders (GRD) developmental and epileptic encephalopathies (DEEs) display a clinical spectrum including developmental delay, hypotonia, intellectual disability, epilepsy, and autistic traits. The presence of de novo pathogenic variants in the <i>GRIN</i> genes alters the <i>N</i>-methyl D-aspartate receptor (NMDAR) function, with a genotype-phenotype relationship. Despite recent advances to elucidate GRD pathophysiological mechanisms and to find treatments, to date, GRD therapeutic arms are still scarce and with limited efficacy. Herein, we investigated whether the natural polyamine spermine—positive allosteric modulators of GluN2B subunit-containing NMDARs—or its precursor spermidine might rescue NMDAR hypofunctionality. In heterologous cell systems, administration of spermine potentiated wild-type and loss-of-function (LoF) NMDAR-mediated currents and attenuated synaptic density deficits. Functionally, the putative therapeutic benefit of spermidine (spermine precursor) was assessed in constitutive <i>Grin2b</i>^+/− heterozygous mice, a GRIN2B-LoF genetic murine model recapitulating GRD-like synaptic, motor, and cognitive alterations. Chronic spermidine administration in young adult <i>Grin2b</i>^+/− mice partially rescued hippocampal long-term potentiation deficits in hippocampal slices of <i>Grin2b</i>^+/− mice, supporting the cognitive improvement observed in behavioral phenotyping. Based on these preclinical findings, a case study was conducted in two pediatric patients harboring mild GRIN2B-LoF variants. Importantly, in line with preclinical findings, 18 months of spermidine treatment resulted in the amelioration of adaptive behavior (notably in the younger treated patient), with the absence of noticeable side effects. Overall, our findings provide both preclinical and clinical data supporting the benefit of spermidine for the treatment of GRD in individuals harboring GRIN2B-LoF variants.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders","authors":"Francis Rossignol,&nbsp;Foudil Lamari,&nbsp;Grant A. Mitchell","doi":"10.1002/jimd.70008","DOIUrl":"https://doi.org/10.1002/jimd.70008","url":null,"abstract":"<p>Phosphatidylinositol, a glycerophospholipid with a <i>myo</i>-inositol head group, can form seven different phosphoinositides (PItds) by phosphorylation at inositol carbons 3, 4 and/or 5. Over 50 kinases and phosphatases participate in PItd metabolism, creating an interconnected PItd network that allows for precise temporal and spatial regulation of PItd levels. We review paradigms of PItd action, including (1) the establishment of subcellular organelle identity by the acquisition of specific PItd signatures, permitting regulation of key processes of cell biology including trafficking (exocytosis, clathrin-dependent and -independent endocytosis, formation and function of membrane contact sites, cytoskeletal remodeling), (2) signaling through phospholipase C cleavage of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and DAG, and (3) roles of PItds in molecular transport at membrane contact sites. To date, variants in 34 genes of PItd metabolism account for at least 41 distinguishable monogenic conditions. Clinical presentations of these disorders produce a broad and often multisystemic spectrum of effects. The nervous system is often involved, and muscular, immunological, skeletal, renal, ophthalmologic and dermatologic features occur in several conditions. Some syndromes involving PItd metabolism can be distinguished clinically, but most diagnoses currently result from broad molecular diagnostic testing performed for the patient's presenting clinical complaint. Genetic disorders of PItd metabolism are a broad, expanding and challenging category of inborn errors. Challenges include improved documentation of the clinical spectra, development of broad biochemical diagnostic methods for these conditions and better understanding of the PItd networks in different cells and subcellular compartments necessary for the development of disease-specific therapies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Trafficking Disorders: Phenotypical Similarities and Differences With Other IMDs”","authors":"Ángeles García-Cazorla,&nbsp;Eva Morava,&nbsp;Jean-Marie Saudubray","doi":"10.1002/jimd.70004","DOIUrl":"https://doi.org/10.1002/jimd.70004","url":null,"abstract":"<div>\u0000 \u0000 <p>Cell trafficking disorders (CTD) are genetic defects in complex molecules and correspond to the largest category of IEM with mutations in more than 370 genes described. They are still poorly recognized as a global entity but rather seen as isolated rare diseases by non-metabolic specialists. Complex lipid metabolism (mostly phospholipids, sphingolipids, and non-mitochondrial fatty acids) is tightly associated with cell trafficking and interactions between organelles at the membrane contact sites. Accordingly, from a clinical point of view CTD presents with multisystem manifestations that may overlap and mimic mitochondrial and other complex molecule disorders such as peroxisomal, lysosomal defects, CDG, or autophagy disorders. The nervous system is especially vulnerable and neurological presentations are prominent, but CTD targets any organ at any age. Interestingly the involvement of the immune system is particularly characteristic of CTD and rarely (or at least little described so far) in other categories of IEM. Most CTD are progressive disorders, except for CDG. They may have “metabolic crises” mimicking disorders of intermediary and energy metabolism for which emergency protocols have been developed. They are generally diagnosed by exome sequencing. Relatively few biomarkers are available.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}